US10435445B2ActiveUtilityA1
Peptide compound

Assignee: TAKEDA PHARMACEUTICALS COPriority: Mar 31, 2017Filed: Mar 30, 2018Granted: Oct 8, 2019
Est. expiryMar 31, 2037(~10.7 yrs left)· nominal 20-yr term from priority
Inventors:Taiji Asami Naoki Nishizawa Ayumu Niida Yoko Kanematsu Mari Adachi Shiro Takekawa Tomoko Morimoto
C07K 14/605C07K 14/4705A61P 1/08A61K 47/60A61K 38/00
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Claims
Abstract

The present invention provides a novel peptide compound having an activating action on GIP receptors and use of the peptide compound as a medicament. Specifically, a peptide containing a sequence represented by the formula (I) or a salt thereof and a medicament comprising the same are provided. (I) P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13- A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25- A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37- A38-A39-A40-P 2 wherein each symbol is as defined herein.
Claims

exact text as granted — not AI-modified
The invention claimed is: 
     
       1. A peptide represented by formula:
 H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH 2  (SEQ ID NO: 12), or a pharmaceutically acceptable salt thereof; or 
 H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Gln-Ala-Gln-Aib-Glu-Phe-Val-Arg-Trp-Leu-Leu-Arg-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 36), or a pharmaceutically acceptable salt thereof; or 
 Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Ile-Ala-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 65), or a pharmaceutically acceptable salt thereof; or 
 Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 110), or a pharmaceutically acceptable salt thereof; or 
 Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 119), or a pharmaceutically acceptable salt thereof; or 
 Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 123), or a pharmaceutically acceptable salt thereof; or 
 Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 (SEQ ID NO: 354), or a pharmaceutically acceptable salt thereof; or 
 Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 (SEQ ID NO: 362), or a pharmaceutically acceptable salt thereof. 
 
     
     
       2. A medicament comprising the peptide according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       3. The medicament according to  claim 2 , which is an activator of a GIP receptor. 
     
     
       4. The medicament according to  claim 2 , which is a suppressant for vomiting or nausea. 
     
     
       5. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 1  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       6. A method for activating a GIP receptor in a mammal, comprising administering an effective amount of the peptide of  claim 1  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       7. The peptide of  claim 1  or a pharmaceutically acceptable salt thereof for use in suppressing vomiting or nausea. 
     
     
       8. The method according to  claim 5 , wherein the vomiting or the nausea is caused by one or more conditions or causes selected from the following (1) to (6):
 (1) diseases such as gastroparesis, gastrointestinal hypomotility, peritonitis, abdominal tumor, constipation, gastrointestinal obstruction, cyclic vomiting syndrome, chronic unexplained nausea and vomiting, acute and chronic pancreatitis, hyperkalemia, cerebral edema, intracranial lesion, metabolic disorder, gastritis caused by an infection, hyperemesis gravidarium, postoperative disease, myocardial infarction, migraine, intracranial hypertension, cannabis hyperemesis syndrome, and intracranial hypotension; 
 (2) drugs such as (i) alkylating agents, cytotoxic antibiotics, antimetabolic agents, vinca alkaloids, other chemotherapeutic agents; (ii) opioid analgesics; (iii) dopamine receptor D1D2 agonists; and (iv) cannabis and cannabinoid products; 
 (3) radiation sickness or radiation therapy used to treat cancers; 
 (4) a poisonous substance or a toxin; 
 (5) pregnancy; and 
 (6) a vestibular disorder. 
 
     
     
       9. A peptide represented by formula:
 H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Glu-Phe-Val-Lys-Trp-Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys-NH 2  (SEQ ID NO: 12), or a pharmaceutically acceptable salt thereof. 
 
     
     
       10. A peptide represented by formula:
 H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Gln-Ala-Gln-Aib-Glu-Phe-Val-Arg-Trp-Leu-Leu-Arg-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 36), or a pharmaceutically acceptable salt thereof. 
 
     
     
       11. A peptide represented by formula:
 Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Ile-Ala-Gln-Gln-Asp-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 65), or a pharmaceutically acceptable salt thereof. 
 
     
     
       12. A peptide represented by formula:
 Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 110), or a pharmaceutically acceptable salt thereof. 
 
     
     
       13. A peptide represented by formula:
 Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 119), or a pharmaceutically acceptable salt thereof. 
 
     
     
       14. A peptide represented by formula:
 Me-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Arg-NH 2  (SEQ ID NO: 123), or a pharmaceutically acceptable salt thereof. 
 
     
     
       15. A peptide represented by formula:
 Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Lys(Eda-GGGGG-)-Asp-Arg-Aib-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2  (SEQ ID NO: 354), or a pharmaceutically acceptable salt thereof. 
 
     
     
       16. A peptide represented by formula:
 Me-Tyr-Aib-Glu-Gly-Thr-Iva-Ile-Ser-Asp-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Lys(Oda-GGGGG-)-Ala-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2  (SEQ ID NO: 362), or a pharmaceutically acceptable salt thereof. 
 
     
     
       17. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 9  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       18. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 10  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       19. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 11  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       20. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 12  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       21. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 13  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       22. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 14  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       23. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 15  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       24. A method for suppressing vomiting or nausea in a mammal, comprising administering an effective amount of the peptide of  claim 16  or a pharmaceutically acceptable salt thereof to the mammal. 
     
     
       25. A medicament comprising the peptide according to  claim 9 , or a pharmaceutically acceptable salt thereof. 
     
     
       26. A medicament comprising the peptide according to  claim 10 , or a pharmaceutically acceptable salt thereof. 
     
     
       27. A medicament comprising the peptide according to  claim 11 , or a pharmaceutically acceptable salt thereof. 
     
     
       28. A medicament comprising the peptide according to  claim 12 , or a pharmaceutically acceptable salt thereof. 
     
     
       29. A medicament comprising the peptide according to  claim 13 , or a pharmaceutically acceptable salt thereof. 
     
     
       30. A medicament comprising the peptide according to  claim 14 , or a pharmaceutically acceptable salt thereof. 
     
     
       31. A medicament comprising the peptide according to  claim 15 , or a pharmaceutically acceptable salt thereof. 
     
     
       32. A medicament comprising the peptide according to  claim 16 , or a pharmaceutically acceptable salt thereof. 
     
     
       33. The method according to  claim 8 , wherein the alkylating agent comprises cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, or melphalan. 
     
     
       34. The method according to  claim 8 , wherein the cytotoxic antibiotic comprises dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, or pirarubicin. 
     
     
       35. The method according to  claim 8 , wherein the antimetabolic agent comprises cytarabine, methotrexate, 5-fluorouracil, enocitabine, or clofarabine. 
     
     
       36. The method according to  claim 8 , wherein the vinca alkaloid comprises etoposide, vinblastine, or vincristine. 
     
     
       37. The method according to  claim 8 , wherein the other chemotherapeutic agent comprises cisplatin, procarbazine, hydroxyurea, azacytidine, irinotecan, interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, or miriplatin. 
     
     
       38. The method according to  claim 8 , wherein the opioid analgesic comprises morphine. 
     
     
       39. The method according to  claim 8 , wherein the dopamine receptor D1D2 agonist comprises apomorphine. 
     
     
       40. The method according to  claim 8 , wherein the intracranial hypotension comprises altitude sickness. 
     
     
       41. The method according to  claim 8 , wherein the vestibular disorder comprises motion sickness or dizziness.
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